Dr. Cheney was an enthusiastic supporter of the XMRV finding early on; he did a webcast on it and several blogs, suggested treatments and provided patients for the WPI to study. In this post from Jan Van Roijen on Co-cure Dr. Cheney reveals the latest on the Lipkin study from a conference call with Dr. Lipkin.

The fact that he – an important ME/CFS physician and thinker – who is not involved with the trials, was on the conference call demonstrates Dr. Lipkin’s commitment to get many of the major elements of the CFS community involved.

What did we learn? The Lipkin study has not officially ‘begun’; ie it has not started collecting samples but is about to, and yes, Dr. Lipkin does expect it to finish up by early next year or sooner (cross your fingers :)).

The study has been expanded since Sept of 2010 when Dr. Lipkin envisioned 100 patients collected from four sites. Now 150 patients will come from six sites (25 patients per site).

Six physicians (Drs. Montoya, Komarroff, Klimas, Enlander (?), Peterson and Bateman) will be providing a total of 150 patient samples to go with the 150 control samples. All the samples will be collected and stored in the same manner. All the reagents used will be tested for contamination.

Each lab will take its own shot at the virus. The WPI will take the strongest shot employing 4 different tests; culture, PCR, western blot with sequencing and serology, Alter/Lo will do PCR on plasma and Switzer will use PCR on extracted DNA.

In these types of studies an independent agent usually stores the codes for the samples. After all the parties report their results the code for each sample will be broken and the researchers will learn what percentage of CFS patients and healthy controls their tests indicated were positives and if any other labs had similar results.

The goal for the WPI will be to find low levels of XMRV in healthy controls (<10%) and find significantly higher levels of XMRV in the patient samples.

Good News For The WPI - The fact that Lipkin will count ANY positive as a positive for each sample is helpful for the WPI since they will be taking the most shots (four) at each sample. Since any positive counts as positive all they have to do is find the bug once out of four times in order for that sample to count as ‘positive’.

Lowering the bar for what is positive (ie multiple positives are not required for a sample to be positive) does bring a danger of false positives as well.

Since the investigators are looking for MLV’s and XMRV there will presumably be two separate sets of results; one for XMRV positives and one for MLV positives.

We can assume that the CDC findings will be negative. If Alter/Lo are using the same methodology as they did in their first study, the best guess is that they will find MLV’s but probably not XMRV.

The most important lab, of course, is the WPI. It doesn’t really matter what the other labs find so long as the samples the WPI finds XMRV in end up mostly belonging to people with CFS and not the healthy controls. If that happens then they’ve proven that they and no one else thus far, knows how to find XMRV and the whole process presumably starts over again, this time with labs using exactly the same methods as the WPI.

Dr. Cheney concluded that Dr. Lipkin is acting in a non-partisan manner and he is fully confident that Dr. Mikovits will turn the tables on much of the rest of the medical establishment stating he

would not want to be Switzer or the CDC or Jay Levy or Singh or John Coffin or the Science editors or most of the UK medical establishment right now. The odds are not in their favor but we will see. I think they are all on the Titanic after what I heard today.

Let the Games Begin….

The entire post is below

‘I and a few other colleagues just completed a large conference call with NIH officials and many interested parties regarding the proposed *Lipkin* study which is poised to soon be launched.

Results are expected by early next year or sooner on 150 CFS cases and 150 matched controls from six centers familiar with CFS (Stanford U., Harvard U., U. Miami, NYC, Incline Village and Salt Lake City).These cases are from three academic centers and three private practices who see CFS cases.

The study, independently agreed upon by three XMRV investigators (WPI-Mikovits, FDA-Lo/Alter and CDC-Switzer), and overseen by Ian Lipkin himself at the NIH will resolve the current disagreements on:

a) the existence of detectable XMRV/MLV in CFS

and

b) the association of XMRV/MLV with CFS.

After listening to about 20 key players on three continents as well as Lipkin himself who appears very non-partisan, there is no doubt in my mind what this study will show with the full backing of the NIH in its outcome and conclusions.

The good thing will be that all reagents will be certified as contaminant free.

All samples will be collected the same way and cases/controls assessed the same way.

In the analysis, though different labs will do *their thing*, they are allowed the methods they choose.

If a sample is positive from any of the three, it will be counted positive and if any sample is negative from all three, it will be counted as negative.

If one sample is positive from one site and negative from the other two, it will be deemed positive for purposes of the study conclusions.

Judy Mikovits will employ four different assays (culture, PCR, western blot with sequencing and serology) while Alter/Lo will employ PCR on plasma and Switzer will use PCR on extracted DNA as sole tests.

May the games begin and the best man or woman win.

If Judy Mikovits can, in a blinded fashion, come to the same conclusions she arrived at before in the Science paper, the sky will fall in on all other naysayers and reputations and egos will suffer great humiliation.

I am confident she will do well and so is she.

If not, the patients are no worse off than before and this disease will remain the enigma it has always been to those who treat it and those who live it.

However, I would not want to be Switzer or the CDC or Jay Levy or Singh or John Coffin or the Science editors or most of the UK medical establishment right now.

The odds are not in their favor but we will see. I think they are all on the Titanic after what I heard today.’

So will all 3 labs be testing all 300 samples? That’s a lot of samples to test, especially for the WPI, with 4 assays, including culture. I’m sure all 3 labs will be using extraordinary precautions against contamination, too. It seems optomistic to think they’ll finish by early next year. But I guess with such high stakes, the labs will be making a big push.

maz has a very good question.. I really hope they have a mechanism to make sure the patients from all 6 centers are chosen according to strict criterias. This is one place where things can quickly go wrong. With 25 patients per center, if a few use vague criterias it will quickly destroy the statistical significance.

We have to make sure the analysis will be performed for each center separately. I thrust Dr Montoya.

I think with Bateman, Klimas, Komaroff, Peterson (???) – not sure who else we’re in good shape. They don’t have to find 70% of samples positive for the study to work out – all they have to do is find significantly higher # of positives in the CFS patients than in the controls. If they found 30-10% I think that would be a win or 40 or 50% to 10% – big win!

Also, I’m skeptical of “If a sample is positive from any of the three, it will be counted positive and if any sample is negative from all three, it will be counted as negative.

If one sample is positive from one site and negative from the other two, it will be deemed positive for purposes of the study conclusions.”

What is that?? The analysis HAS TO BE done separately for each of the 3 testing centers. This is non-negationable. If Alter/Lo are looking for a pathogen somewhat different from WPI, all the CDC has to do is report positive the controls and negative the patients and the whole study now means absolutely nothing. Yes my friends the CDC has and will continue to play dirty. And even without the CDC playing dirty if the analysis is not performed for each center separately the statiscial significance will be gone if the CDC reports everyone negative.

The analysis has to be done separately for each center – I don’t see how it could work otherwise. I don’t think what the other labs do really matters – its all about the WPI…if they can nab those samples right they’ll do fine.

You say I don’t see how it could work otherwise – I agree. That’s why I was very surprised to read that Dr Cheney said “If a sample is positive from any of the three, it will be counted positive and if any sample is negative from all three, it will be counted as negative.

If one sample is positive from one site and negative from the other two, it will be deemed positive for purposes of the study conclusions.”

We absolutely can’t let this study be corrupted and then look back regretting not having taken action when it was still time. The protocol has to be fool proof, 100% transparent, from the parties involved. This is like a cryptography protocol, we can’t allow any step of the data transfer/processing to be corruptible.

I don’t know what the parameters are. I have the feeling they are out there. Usually in studies like this – where they just want to validate the finding – physicians will choose the patients they feel are most likely to test positive and I imagine that’s what’s happening here. So you may have relatively light parameters – meet the criteria for Fukuda – with alot of really sick patients loaded in there.

I think the criteria are going to be kind of complex. From what I remember reading/piecing together from various sources, patients will meet ‘all’ of the criteria, ie the Canadian (since patients will automatically meet the Fukuda if they meet Canadian criteria) with it’s mandatory PEM, cognitive disturbances, etc, and will also have to have had a sudden, infectious onset. It’s going to be kind of a tailor-made CFS definition where there’s no doubt that the patients have CFS. However the sudden onset part is the part that actually doesn’t make much sense to me as I’m not aware that HIV or HTLV have any sort of killer, flu-like onset, so why would XMRV/MLV’s? There’s a whole contingent of CFS patients with gradual onset, wouldn’t it be ironic if they were the ones with MLV infections?

I’m doubting the WPI and FDA will be able to differentiate cases from controls though, at least with PCR, to me the real question is going to revolve around the serology tests. If CFS patients from numerous centers located around the country have these antibodies significantly more often than controls, it seems like that alone would be enough to keep the whole XMRV/MLV thing active for years to come, even if they ended up being cross-reactive antibodies. The question would be cross-reactive to what?

You are right Skeptical – you read more closely than me….I have to think that Cheney was being sloppy. A major purpose of the test is to compare results between the groups.

As it plays out – it may not matter that much if the CDC doesn’t find anything and Lo/Alter find MLV’s and not XMRV. If that happens then only the WPI will find XMRV – which is about what we expect – and then they’ll see just who they found XMRV in…I can’t imagine what the tension will be like when they break those codes. I think I would have to be lying down.

I thought some of the positive samples WPI found for the original Science paper were going to used and blinded. If this isn’t the case all samples sent out could be XMRV free, how are the samples blinded if they aren’t using known positive samples?

The samples in the Lipkin study are from CFS patients diagnosed by longtime CFS physicians- Klimas, Montoya, Peterson, Levine, Bateman and Komaroff, with Klimas and Peterson being co-authors of the Canadian criteria for CFS. From what I understand, all patients will be required to have post-exertional malaise, sudden onset, sore throat, swollen lymph nodes, etc, which means that the criteria for the Lipkin study is actually stricter than the Canadian criteria, as you can be diagnosed according to the Canadian criteria without several of these criteria. The original WPI study used patients from several CFS physicians located around the country diagnosed according to the Canadian criteria and WPI personnel have stated several times that ‘there was nothing special about the patients’ included in their study, with these statements being made in response to mistaken criticisms that all patients in the original study came from one outbreak area in Incline Village, NV.

The purpose of the Lipkin study is to evaluate whether XMRV is present in the human population and if so, whether it is associated with CFS in particular. The samples will be blinded to all involved. The entire point of the study is to see whether XMRV really exists in the population at all, ie whether there really is such a thing as a ‘known positive’, or whether the original findings are the result of contamination as many have suggested. They can’t use samples collected previously in this study due to one of the greatest strengths of this study being that all samples are collected at the same time, by and from the same individuals at the same location, etc., and are processed and handled in exactly the same manner using the same reagents, tubes, vials, needles, extraction procedures, etc, thereby doing as much as possible to eliminate the possibility of contamination of any sort to enter the process at any point in time. The patient samples in both the WPI’s XMRV and the Alter/Lo MLV studies were collected and stored in a different manner at different points in time than the control samples, which could have potentially affected the results of both studies. The Lipkin study is designed from the outset to do as much as possible to eliminate such concerns.

Yes they did and Dr. Klimas has shown cytokine changes in her patients and so have the Lights. The problem with the cytokine results is they have tended to be all over the map; different researchers have found different things and several have found few changes – how everything will end up is still unclear.

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